Clinical activity and tolerability of the RET inhibitor BLUE-667 in patients with advanced RET fusion and NSCLC

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Published: 6 Jun 2019
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Dr Justin F. Gainor - Massachusetts General Hospital, Boston, USA

Dr Justin F. Gainor talks to ecancer at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting about the results from a study examining the clinical activity and tolerability of the RET inhibitor BLUE-667 in patients with advanced RET fusion and NSCLC.

He explains that 120 patients were included for the safety portion and it was seen that BLUE-667 was well tolerated mostly grade 1 and 2 side effects.

Dr Gainor reports that promising activity was seen in patients with RET fusion positive NSCLC and within the subset of 48 patients with valuable disease there was an overall response rate of 58%.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

Oncogenic rearrangements involving RET occur in approximately 1-2% of patients with non-small cell lung cancer. RET rearrangements define a distinct molecular subset of the disease. These patients are typically never smokers and RET rearrangements don’t really overlap with other oncogenic drivers in lung cancer. When RET rearrangements were first discovered in lung cancer around 2012 there were efforts to target it and at the time people tried repurposing a lot of multi-kinase inhibitors that just happened to have RET activity. Unfortunately, those trials, mainly single arm studies, showed relatively modest activity in RET rearranged lung cancer. So we were seeing response rates around 20-30%.

With that background and knowing that these patients have relatively modest benefits from other forms of therapy, namely chemotherapy, BLUE-667 was developed. BLUE-667 is a selective RET inhibitor so it’s specifically designed to target RET. It’s greater than 90 times more selective for RET versus VEGF which was a target of many of those other multi-kinase inhibitors. In pre-clinical models BLUE-667 is highly active in RET rearranged lung cancer models as well as in models involving RET point mutations, so medullary thyroid cancer models. Importantly, in addition to the activity that BLUE-667 has on RET fusion driven models it also has activity against the gatekeeper mutation in RET which is V804, at least pre-clinical activity.

So with that background a phase I study was launched and it had two different parts. Part 1 was the dose escalation phase; that was completed last year. It involved a little over 60 patients and identified the recommended phase II dose of 400mg once a day. So what I’ll be presenting is looking at BLUE-667 in the part 2 of the study which is focussed on patients with RET fusion positive lung cancer.

Altogether about 120 patients were included for the safety portion, all of these patients were treated at the recommended phase II dose of 400mg. We see that in general BLUE-667 is quite well tolerated with predominantly grade 1/2 side effects. In total 7% of patients required discontinuation of therapy due to adverse events.

In terms of efficacy we did see very promising activity within RET fusion positive lung cancer, so within the subset of 48 patients who have evaluable disease at the data cut-off we saw an overall response rate of 58% and in patients who had received prior platinum we saw an impressive response rate of 60%. When we focussed on the subgroup of patients with treatment naïve disease we saw five out of seven of those patients actually had objective responses, all of which were confirmed. Importantly, this study also showed evidence of intracranial activity. So among patients who had RECIST measurable brain metastases we actually saw tumour shrinkage in a majority of those patients. So altogether this really demonstrates that BLUE-667 is a very promising drug for RET fusion positive lung cancer.

In your opinion why have there not been any approved RET inhibitors to date? How is BLUE-667 different from the others?

The reason other RET inhibitors haven’t been approved to date was the earlier generations of RET inhibitors were really these multi-kinase inhibitors where they targeted multiple things. Examples of those would be cabozantinib, vandetanib and in single arm studies they showed only modest effects with high degrees of toxicity so frequent dose reductions, frequent dose interruptions.

It was really post-2012 when we actually knew RET fusions were actually present in lung cancer where people, companies, have tried to develop more selective RET inhibitors that spare that VEGF inhibition. So right now there are two selective RET inhibitors that are in clinical trials. We’ve talked about BLUE-667 the other being LOXO-292. Both of these agents were designed to specifically target RET.

What are the next steps for this research?

The next steps are to continue the ongoing phase I study; this study is still enrolling patients. There are several other cohorts, most notably there is a cohort for treatment naïve patients or platinum naïve patients. So gaining more data on patients who are treatment naïve, as I mentioned there are only seven so far, gaining more data in that space will be important. We’ve seen all along in the targeted therapy paradigm in lung cancer that if you have one of these oncogenic driver mutations really targeted therapy should be the priority. So gaining more clinical data in that space will be important.